Transcriptional basis of embryonic macrophage development

胚胎巨噬细胞发育的转录基础

• 批准号: 10531441
• 负责人: Kenneth M Murphy
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531441
• 关键词: ATAC-seq; Ablation; Adult; Amyloid; Area; Binding; Biological Models; Birth; Bone Marrow; Brain; CRISPR/Cas technology; Cells; Data; Defect; Dendritic Cells; Development; Embryo; Embryonic Development; Enhancers; Evaluation; Extracellular Protein; Fetal Development; Fetal Liver; Gene Expression; Genes; Genetic; Genetic Transcription; Heart; Hematopoiesis; Homeostasis; Immune; Immunity; Knowledge; Kupffer Cells; Life; Liver; Lung; Methods; Microglia; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Neuraxis; Pathway interactions; Play; Population; Process; Proteins; Publications; Publishing; Reporter; Risk; Role; Site; Skin; Supporting Cell; System; Testing; Thalassemia; Tissues; Work; Yolk Sac; base; blastomere structure; brain tissue; fetal; in vivo; macrophage; model design; monocyte; novel; prevent; progenitor; programs; repaired; stem; success; tau Proteins; transcription factor; virtual

ABSTRACT It has been appreciated recently that tissue-resident macrophages (TRMs) contribute to tissue homeostasis. For example, in the brain, microglia have been proposed to process extracellular proteins and to restrict the formation of plaque formed from proteins such as -amyloid and Tau proteins. Such tissue-resident macro- phages were once thought to be derived from monocytes that arise in definitive hematopoiesis in the adult bone marrow. However, we now understand that TRMs are derived during fetal life and arise from progenitors in the yolk sac and fetal liver. In some tissues, these embryonically derived macrophage populations persist throughout adult life and are not efficiently replaced by circulating monocytes arising from adult bone marrow and definitive hematopoiesis. One impediment to studying the functions of such embryonically derived macro- phages is the relative paucity of information regarding their development, specifically the transcriptional pro- grams that guide their development. The lack of such information prevents the design of model systems where these cells can be prevented from developing, which would allow their in vivo functions to be defined in a defin- itive way. The current application is aimed at defining the basis for the embryonic development of macrophag- es. It is based on preliminary data that has: 1) identified the Zeb2 enhancer (at -165kb) used in definitive hematopoiesis supporting monocyte/macrophage development from the adult bone marrow; 2) showed that this enhancer is not required for Zeb2 expression in embryonic macrophage development, and 3) identified two other Zeb2 enhancers that are selectively active in the embryonic yolk sac and fetal liver progenitors. This application will (Aim 1) test these embryonically active Zeb2 enhancers for their role in supporting embry- onic macrophage development, and (Aim 2) determine the transcriptional basis for their embryonic activity. Aim 1 may directly produce models of embryonic macrophage deficiency, which would immediately benefit re- search in other areas related to immune cell support of tissue homeostasis. Beyond this, the basic information on the similarities or differences between primitive and adult hematopoiesis could have further uses, such as in adding to ways in which fetal gene expression can be controlled to compensate for innate or acquired defects in adult gene expression, such as in -thalassemia.

抽象的 最近人们认识到组织驻留巨噬细胞（TRM）有助于组织稳态。 例如，在大脑中，小胶质细胞被认为可以处理细胞外蛋白质并限制 由 β-淀粉样蛋白和 Tau 蛋白等蛋白质形成的斑块的形成。这种组织驻留宏 噬菌体曾经被认为源自成人确定性造血过程中产生的单核细胞 骨髓。然而，我们现在了解到 TRM 源自胎儿生命期间并由祖细胞产生 在卵黄囊和胎儿肝脏中。在某些组织中，这些胚胎衍生的巨噬细胞群持续存在 在整个成年生命中，并且不能被成人骨髓产生的循环单核细胞有效替代 和确定的造血作用。研究这种胚胎衍生的宏观功能的障碍之一是 噬菌体的发展信息相对较少，特别是转录亲 指导他们发展的克。缺乏此类信息会阻碍模型系统的设计 这些细胞可以被阻止发育，这将允许它们的体内功能被定义在一个定义中。 主动方式。目前的申请旨在确定巨噬细胞胚胎发育的基础 es.它基于以下初步数据：1) 确定了最终使用的 Zeb2 增强子（-165kb） 支持成人骨髓中单核细胞/巨噬细胞发育的造血作用； 2）表明 该增强子对于胚胎巨噬细胞发育中的 Zeb2 表达来说不是必需的，并且 3) 鉴定了两个 其他在胚胎卵黄囊和胎儿肝脏祖细胞中选择性活跃的 Zeb2 增强子。 该应用程序将（目标 1）测试这些胚胎活性 Zeb2 增强剂在支持胚胎发育中的作用。 离子巨噬细胞的发育，以及（目标 2）确定其胚胎活性的转录基础。 目标 1 可能会直接产生胚胎巨噬细胞缺陷模型，这将立即有利于重新研究。 搜索与免疫细胞支持组织稳态相关的其他领域。除此之外，还有基本信息 关于原始造血和成人造血之间的相似性或差异可能有进一步的用途，例如 添加控制胎儿基因表达以补偿先天或后天缺陷的方法 成人基因表达，例如  地中海贫血。